JP6273072B2 - Compositions and methods of treating cardiac fibrosis with ifetroban - Google Patents

Description

Field of the Invention The present invention is a mammal, for example, thromboxane A ₂ receptor antagonists in the treatment and / or prevention of fibrosis in humans (e.g., ifetroban (Ifetroban)) used, and thromboxane A ₂ receptor antagonist It relates to a pharmaceutical composition for an equivalent comprising a drug (eg ifetroban) in an amount effective to treat and / or prevent these diseases. In certain embodiments, the fibrosis is cardiac fibrosis.

BACKGROUND OF THE INVENTION Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue during a repair or reaction process. This may be a reactive state, benign state or pathological state and acts physiologically to deposit connective tissue that may destroy the structure and function of the underlying organ or tissue . Fibrosis can be used to describe the pathological state of excessive deposition of fibrous tissue, as well as the process of connective tissue deposition during healing. Fibrous tissue formation is normal and fibrous tissue is a normal component of internal organs or tissues, whereas scars caused by fibrotic conditions can destroy the structure of the underlying organ or tissue There is.

  For example, when fibrotic scar tissue is replaced by myocardium damaged by hypertension, the heart is less elastic and therefore less capable of working. Similarly, pulmonary fibrosis stiffens the lungs and damages lung function. Fibrosis growth can proliferate and infiltrate healthy surrounding tissue even after the original injury has healed. In most cases, fibrosis is a reactive process, and several different factors can clearly regulate the pathways leading to tissue fibrosis. Such factors include early inflammatory responses, local increases in the fibroblast population, regulation of fibroblast synthesis function, and regulatory changes in collagen biosynthesis and degradation. Other factors include inflammation of nearby tissues or inflammatory conditions generated with increased circulating mediators.

  Fibrosis includes pathological conditions characterized by abnormal and / or excessive accumulation of fibrotic substances (eg, extracellular matrix) with tissue damage. Fibroproliferative diseases are vascular diseases such as heart disease, brain disease, and peripheral vascular disease, as well as various chronic diseases that affect the lung, kidney, eye, heart, liver, digestive system and skin. It is the cause of morbidity and mortality associated with organ failure.

  To date, there are no commercially available treatments that are effective for treating or preventing fibrotic diseases, particularly cardiac fibrosis. Conventional treatment of most fibrosis-related disorders frequently involves corticosteroids such as prednisone and / or other drugs that suppress the body's immune system. The goal of current treatment regimens is to reduce inflammation and subsequent scarring. Responses to currently available treatments are variable and the toxicity and side effects associated with these treatments can be significant. In fact, only a few patients respond to corticosteroids alone, and immunosuppressive drugs are often used in combination with corticosteroids.

  Right ventricular (RV) failure is a leading cause of death in pulmonary arterial hypertension (PAH) and a significant source of morbidity and mortality in other forms of pulmonary hypertension. Production of thromboxane and F2 isoprostane, both thromboxane / prostainoid (TP) receptor agonists, is increased in pathological conditions that increase stress stress such as pulmonary arterial hypertension The Prostacyclin / thromboxane balance has been associated with cardioprotective effects under stress, possibly through coronary support. While aspirin treatment can reduce both thromboxane and prostaglandin production, aspirin treatment suppresses beneficial prostacyclin production and has no effect on isoprostane formation.

  There is no approved treatment indicated when protecting RV function. F-series and E-series isoprostanes are increased in heart failure and PAH and are associated with disease severity and may have effects from vasoconstriction to fibrosis that may be demonstrated through thromboxane / prostanoid (TP) receptors. Accompany. The decrease in RV function can progress despite treatment that lowers pulmonary artery pressure. RV response to chronic pressure overload can be both adaptive and non-adaptive, which often determines clinical outcome. Adaptive ventricular hypertrophy with increased protein synthesis maintains function, while fibrosis and cardiomyocyte hypertrophy can cause arrhythmias and systolic dysfunction, and incompatible dilation is associated with RV dysfunction. Thus, treatment strategies that promote adaptive hypertrophy in the face of chronic stress can protect cardiac function and improve performance.

The development of cellular hypertrophy and myocardial fibrosis that occurs with chronic pressure loading is also associated with increased oxidative stress and lipid peroxidation. 15-F _2t isoprostane (8-isoPGF _2α or 8-isoF) is a common biomarker for oxidative stress, the level of which increases with ventricular dilatation and is associated with the severity of heart failure. In addition to being a biomarker, it is suggested that 8-isoF and other isoprostanes may play a direct role in cardiomyopathy. The F-series and E-series isoprostanes are known to signal through thromboxane / prostanoid (TP) receptors and the effects range from vasoconstriction to fibrosis. Cyclooxygenase (COX) products of cyclic endoperoxide (PGH ₂ ) and thromboxane A ₂ (TxA ₂ ) are also ligands for TP receptors, and TP receptor activation contributes to cardiac hypertrophy in models of chronic hypertension Reduces cardiac function in Gh-overexpressing mice. TP receptors are found not only in platelets and blood vessels, but also in the right ventricle where receptor density is increased in PAH patients.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a new method for preventing and / or treating fibrosis and / or sclerosis in mammals such as humans.

  It is an object of the present invention to provide compositions and methods for preventing and / or treating and / or alleviating cardiac fibrosis in mammals such as humans.

  It is yet another object of the present invention to provide compositions and methods for reducing the effects of cardiac fibrosis in mammals such as humans.

It has now been unexpectedly discovered that treatment of mammals with a therapeutically effective amount of a thromboxane A ₂ receptor antagonist (e.g., ifetroban) can prevent or reduce cardiac fibrosis and related sequelae Has been. In certain embodiments, administration of a therapeutically effective amount of a thromboxane A ₂ receptor antagonist (e.g., ifetroban) is performed under conditions of pressure overload from inflammation and fibrosis to functional physiological hypertrophy and cardiomyopathy and Heart failure can be prevented or reduced.

  In view of the above, the present invention provides a patient in need of a therapeutically effective amount of a thromboxane A2 receptor antagonist (e.g., ifetroban or a pharmaceutically acceptable salt thereof (e.g., ifetroban sodium)). Administration provides a method for preventing, reversing, ameliorating or treating fibrosis.

  With the above objectives, the present invention prevents, reverses, improves cardiac fibrosis by administering to patients in need thereof a therapeutically effective amount of a thromboxane A2 receptor antagonist (e.g., ifetroban). A method of doing or treating is provided.

In certain embodiments, the present invention provides for a desired plasma concentration of about 0.1 ng / ml to about 100,000 ng / ml thromboxane A ₂ receptor antagonist (and / or its active metabolite). A method of treating and / or ameliorating a fibrotic disease or condition in a patient, particularly cardiac fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of a thromboxane A ₂ receptor antagonist To do. In certain embodiments, the therapeutically effective amount of thromboxane A2 receptor antagonist to provide a desired plasma concentration of thromboxane A2 receptor antagonist is from about 0.1 ng / ml to about 10,000 ng / ml. It is. In some embodiments, the plasma concentration is a steady state plasma concentration. In some embodiments, the plasma concentration is the maximum plasma concentration (Cmax). In certain preferred embodiments, the thromboxane A2 receptor antagonist is ifetroban or a pharmaceutically acceptable salt thereof, such as ifetroban sodium.

The present invention is also directed to a method of providing cardioprotective effects to a human patient experiencing pulmonary arterial hypertension through administration of a thromboxane A ₂ receptor antagonist as described herein.

The present invention is further directed to a method of improving right heart adaptation to stress stress in a human patient through administration of a thromboxane A ₂ receptor antagonist as described herein.

In certain embodiments, the thromboxane A ₂ receptor antagonist comprises a therapeutically effective amount of [1S- (1α, 2α, 3α, 4α)]-2-[[3- [4-[(pentylamino) Carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] methyl] -benzenepropanoic acid (ifetroban), and pharmaceutically acceptable salts thereof.

The present invention further provides therapeutically effective amounts of [1S- (1α, 2α, 3α, 4α)]-2-[[3- [4-[(pentylamino) carbonyl] -2-oxazolyl] -7- In mammals in need of their treatment, including administering to a mammal oxabicyclo [2.2.1] hept-2-yl] methyl] -benzenepropanoic acid (ifetroban) or a pharmaceutically acceptable salt thereof Further directed to methods of treating cardiac fibrosis. In certain embodiments, the thromboxane A ₂ receptor antagonist comprises a therapeutically effective amount of [1S- (1α, 2α, 3α, 4α)]-2-[[3- [4-[(pentylamino) Carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] methyl] -benzenepropanoic acid monosodium salt (ifetroban sodium). In certain preferred embodiments, a therapeutically effective amount of ifetroban reduces the rate of formation of fibrotic tissue in a mammal. In certain preferred embodiments, the mammal is a human patient. In certain preferred embodiments, a therapeutically effective amount of ifetroban delays the progression of myocardial fibrosis in a human patient and / or improves exercise capacity in a human patient and / or reduces RV fibrosis in a human patient. Decrease and / or decrease cardiomyocyte hypertrophy in human patients and / or increase E / A ratio in human patients and / or increase cardiomyocyte diameter in human patients and / or right ventricular ejection Rate (RVEF: right ventricular ejection fraction), left ventricular ejection fraction (LVEF), pulmonary dynamics, right ventricular systolic pressure (RVSP), left ventricular systolic function (LVSF), right Improve or maintain a function selected from the group consisting of right ventricular diastolic function (RVDF) and left ventricular diastolic function (LVDF).

  In certain preferred embodiments, the therapeutically effective amount of ifetroban is cardioprotective against pressure overload by directing the right heart to adaptation rather than maladaptive fibrosis, inflammation and cellular hypertrophy .

  In certain preferred embodiments, the therapeutically effective amount of ifetroban reduces left heart failure in human patients.

  In any of the methods described above and others described herein, ifetroban is preferably about 1 ng / ml to about 100,000 ng / ml ifetroban (and / or an active metabolite of ifetroban). Or for ifetroban itself in an amount effective to provide a plasma concentration of about 1 ng / ml to about 10,000 ng / ml, and in some embodiments about 1 ng / ml to about 1,000 ng / ml is there. In some embodiments, the plasma concentration is a steady state plasma concentration. In some embodiments, the plasma concentration is a maximum plasma concentration (Cmax). In certain preferred embodiments where the mammal is a human patient, the therapeutically effective amount is from about 100 mg to about 2000 mg per day, or from about 10 mg or about 100 mg to about 1000 mg per day, in certain embodiments, Preferred is about 100 to about 500 mg per day. The daily dose can be administered in divided doses, or in a single bolus dose or unit dose, or in multiple doses administered simultaneously. In this regard, ifetroban can be administered orally, intranasally, rectally, vaginally, sublingually, buccal, parenterally or transdermally.

The present invention further provides a pharmaceutical composition comprising a thromboxane A ₂ receptor antagonist (e.g., ifetroban or a pharmaceutically acceptable salt thereof), wherein the thromboxane A ₂ receptor antagonist requires Right ventricular ejection fraction (RVEF), left ventricular ejection fraction (LVEF), pulmonary dynamics, right ventricular systolic pressure (RVSP), left ventricular systolic function (LVSF), right ventricular diastolic function (RVDF) in mammals And a pharmaceutical composition in an amount effective to improve or maintain a function selected from the group consisting of left ventricular diastolic function (LVDF). In certain preferred embodiments, the ifetroban salt is ifetroban sodium.

  In certain preferred embodiments, in the pharmaceutical compositions described above, the therapeutically effective amount is about 10 mg to about 1000 mg ifetroban (or a pharmaceutically acceptable salt thereof) per day. In certain preferred embodiments, the therapeutically effective amount is from about 100 to about 500 mg per day.

The present invention involves the administration of a therapeutically effective amount of a thromboxane A ₂ receptor antagonist to the subject (s) or patient (s) in need thereof, particularly for the treatment of cardiac fibrosis And methods and compositions for treating fibrosis in a subject or patient in need thereof. In particular, the present invention administers a composition comprising a therapeutically effective amount of a thromboxane A ₂ receptor antagonist to a patient in need thereof in an amount effective to reduce the rate of fibrosis or sclerosis. A method of treating or preventing a disorder causing fibrosis or sclerosis in a subject (s) or patient (s) in need of such treatment. Further provided is administration of a composition comprising a thromboxane A ₂ receptor antagonist in an amount effective to reduce the formation of fibrotic or sclerotic tissue that occurs in the absence of such treatment. A method of preventing fibrosis or sclerosis in a subject or patient in need of such treatment.

  In certain embodiments, the fibrosis is associated with a fibroproliferative disease selected from the group consisting of cardiac fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis and systemic sclerosis.

For purposes defined in the detailed description of the invention , a therapeutically effective amount of a thromboxane A ₂ receptor antagonist is administered to a subject or patient in need of fibrosis (a fibrosis disease or condition, In particular, it is considered that (heart fibrosis) can be prevented and / or treated.

  The inability of the right ventricle to adapt to stress stress is a direct cause of death in pulmonary arterial hypertension. Thromboxane production is increased in pathological conditions that increase stress stress such as pulmonary arterial hypertension, and prostacyclin / thromboxane balance has been associated with cardioprotective effects under stress, possibly through coronary support. Aspirin treatment can reduce the production of both thromboxane and prostaglandins, but also suppresses beneficial prostacyclin production and may require more targeted approaches.

  Fibrosis can occur in many tissues in the body, typically as a result of inflammation or damage, such as: pulmonary fibrosis (lung); idiopathic pulmonary fibrosis (where the cause is unknown) Cystic fibrosis; liver fibrosis or cirrhosis (liver); cardiac fibrosis including endocardial myocardial fibrosis (heart), old myocardial infarction (heart), atrial fibrosis (heart); And other, including but not limited to mediastinal fibrosis (mediastinal soft tissue), myelofibrosis (bone marrow), retroperitoneal fibrosis (retroperitoneal soft tissue), progressive massive fibrosis (lung) Fibrosis condition; pneumoconiosis in coal miners, renal systemic fibrosis (skin), Crohn's disease (intestine), keloid (skin), scleroderma / systemic sclerosis (skin, lung), arthritis ( Complications of the knee, shoulders, other joints) and certain forms of adhesive arthritis (shoulders). Other names for the various types of pulmonary fibrosis that have been used in the past include chronic interstitial pneumonia, Haman-Rich syndrome, conventional interstitial pneumonia (UIP), and diffuse fibrotic alveolitis Is mentioned.

  Symptoms of pulmonary fibrosis include shortness of breath, cough, and decreased exercise tolerance. The severity of symptoms over time and the worsening of symptoms can vary and depend at least in part on the cause of fibrosis.

  Cirrhosis is an extensive scar (fibrosis) in the liver caused by long-term damage. This damage is caused by inflammation, which is a normal response to some damage, such as chronic viral infection or chronic alcohol dependence. The liver repairs damaged areas by replacing those damaged areas with scar tissue in a manner similar to the scar tissue that occurs during the healing process when the subject maintains a cut on their body. . Fibrosis in the liver is different from the surrounding healthy liver tissue. Unfortunately, scar tissue cannot function as normal hepatocytes, so too much scar tissue interferes with basic liver function. Cirrhosis has many causes, but the most common are alcohol dependence and chronic hepatitis. Some other causes of cirrhosis are liver and gallbladder bile duct obstruction, autoimmune hepatitis, and genetic disorders such as Wilson's disease or hemochromatosis.

  Liver fibrosis is a scar process initiated in response to chronic liver disease (CLD) caused by continuous and repeated invasion of the liver. The late stages of CLD involve extensive remodeling of liver constructs and chronic organ failure regardless of the underlying disease (e.g. cirrhosis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC)) Is characterized by

  Idiopathic pulmonary fibrosis (IPF) is the major form of pulmonary fibrosis. IPF is a debilitating and life-threatening lung disease characterized by progressive lung scarring that inhibits oxygen uptake.

  Systemic sclerosis is a degenerative disorder where hyperfibrosis occurs in multiple organ systems including skin, blood vessels, heart, lungs and kidneys. Several forms of fibrosis cause death in scleroderma patients, including pulmonary fibrosis, congestive heart failure and renal fibrosis; each of which occurs in about half of systemic sclerosis patients.

  Fibrosis is also a major cause of organ transplant rejection.

  The phrase “therapeutically effective amount” refers to the amount of a substance that produces some desired local or systemic effect at a reasonable benefit / risk ratio available for any treatment. The effective amount of such substances will vary with the subject to be treated and the disease state, the weight and age of the subject, the severity of the disease state, the means of administration, etc., and can be readily determined by one skilled in the art.

As used herein, the term `` thromboxane A2 receptor antagonist '' is at least 30%, 35%, 40% when used in a standard bioassay or in vivo or at a therapeutically effective dose, Up to 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, or At least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, It refers to compounds that inhibit 98%, 99% or 100% thromboxane receptor expression or activity. In certain embodiments, thromboxane A2 receptor antagonist, to inhibit binding to the receptor of thromboxane A _2. Thromboxane A2 receptor antagonists include competitive antagonists (ie, antagonists that compete with agonists for the receptor) and non-competitive antagonists. Examples of thromboxane A2 receptor antagonists include antibodies to the receptor. The antibody can be monoclonal. They can be human or humanized antibodies. Thromboxane A2 receptor antagonists also include thromboxane synthase inhibitors and compounds having both thromboxane A2 receptor antagonist activity and thromboxane synthase inhibitor activity.
Thromboxane A ₂ receptor antagonist

The discovery and development of thromboxane A ₂ receptor antagonists has been the goal of many pharmaceutical companies for approximately 30 years (see Dogne JM et al., Exp. Opin. Ther. Patents 11: 1663-1675 (2001)). I want to be) Specific individual compounds identified by these companies, with or without concomitant thromboxane A ₂ synthase inhibitory activity, include ifetroban (BMS), ridogrel (Janssen), terbogrel (BI) UK-147535 (Pfizer), GR32191 (Glaxo) and S-18886 (Servier). Preclinical pharmacology has established that this class of compounds has an effective antithrombotic activity obtained by inhibition of the thromboxane pathway. These compounds, thromboxane A _2, and also thromboxane A ₂ receptor vessels induced by other prostanoids acting at the contraction of the vascular bed to prevent, therefore, preventing the hepatorenal syndrome and / or hepatic encephalopathy And / or may be beneficial for use to treat.

Suitable thromboxane A ₂ receptor antagonists for use in the present invention include, but are not limited to, for example, ifetroban (BMS; [1S- (1α, 2α, 3α, 4α)]-2-[[ Small molecules such as 3- [4-[(pentylamino) carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] methyl] benzenepropanoic acid), and US Patent Application Publication No. 2009 Others may be mentioned as described in US / 0012115, the entire disclosure of which is incorporated herein by reference.

  Additional thromboxane A2 receptor antagonists suitable for use herein include U.S. Pat.Nos. 4,839,384 (Ogletree), 5,066,480 (Ogletree et al.), 5,100,889 (Misra et al.), 5,312,818 ( Rubin et al., 5,399,725 (Poss et al.), And 6,509,348 (Ogletree), the entire disclosures of which are incorporated herein by reference. These may include, but are not limited to, interphenylene 7-oxabicyclo-heptyl substituted heterocyclic amide prostaglandin analogs as disclosed in U.S. Patent No. 5,100,889, including:

  [1S- (1α, 2α, 3α, 4α)]-2-[[3- [4-[[(4-cyclohexylbutyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] -Hept-2-yl] methyl] benzenepropanoic acid (SQ33,961) or an ester or salt thereof;

  [1S- (1α, 2α, 3α, 4α)]-2-[[3- [4-[[[(4-Chlorophenyl) -butyl] amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2 .1] hept-2-yl] methyl] benzenepropanoic acid or an ester or salt thereof;

  [1S- (1α, 2α, 3α, 4α)]-3-[[3- [4-[[(4-cyclohexylbutyl) -amino] carbonyl] -2-oxazolyl] -7-oxabicyclo] 2.2.1 ] Hept-2-yl] benzeneacetic acid or its ester or salt;

  [1S- (1α, 2α, 3α, 4α)]-[2-[[3- [4-[[(4-Cyclohexyl-butyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2. 1] hept-2-yl] methyl] phenoxy] acetic acid or an ester or salt thereof;

  [1S- (1α, 2α, 3α, 4α] -2-[[3- [4-[[(7,7-Dimethyloctyl) -amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -methyl] benzenepropanoic acid or an ester or salt thereof.

  [1S- [1α, 2α (Z), 3α, 4α)]-6- [3- [4-[[((disclosed in U.S. Pat. No. 5,100,889) published on Mar. 31, 1992. 7-oxabicycloheptyl substitution including 4-cyclohexylbutyl) amino] -carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] -4-hexenoic acid or its ester or salt Heterocyclic amide prostaglandin analogues;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[(4-cyclohexyl-butyl) amino] carbonyl] -2-thiazolyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[(4-cyclohexyl-butyl) methylamino] carbonyl] -2-oxazolyl] -7-oxabicyclo -[2.2.1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[(1-Pyrrolidinyl) -carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] Hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[(cyclohexylamino) -carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hepta -2-yl-4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[(2-cyclohexyl-ethyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[[2- (4-Chlorophenyl) ethyl] amino] carbonyl] -2-oxazolyl] -7- Oxabicyclo- [2.2.1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]-6- [3- [4-[[(4-Chlorophenyl) -amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[[4- (4-Chlorophenyl) butyl] amino] carbonyl] -2-oxazolyl] -7- Oxabicyclo- [2.2.1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [11α, 2α (Z), 3α, 4α)]]-6- [3- [4α-[[-(6-cyclohexyl-hexyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[(6-Cyclohexyl-hexyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α]]-6- [3- [4-[(propylamino) -carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hepta- 2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[(4-Butylphenyl) -amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[(2,3-Dihydro-1H-indol-1-yl) carbonyl] -2-oxazolyl]- 7-oxabicyclo (2.2.1) hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[(4-cyclohexyl-butyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -N- (phenylsulfonyl) -4-hexenamide;

  [1S- [11α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[(4-cyclohexyl-butyl) amino] carbonyl] -2-oxazolyl] -N- (methylsulfonyl ) -7-oxabicyclo [2-.2.1] hept-2-yl] -4-hexenamide;

  [1S- [1α, 2α (Z), 3α, 4α)]]-7- [3- [4-[[(4-cyclohexyl-butyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -5-heptenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[(4-cyclohexyl-butyl) amino] carbonyl] -1H-imidazol-2-yl] -7 -Oxabicyclo- [2.2.1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α, 3α, 4α)]-6- [3- [4-[[(7,7-Dimethyloctyl) -amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- [1α, 2α (E), 3α, 4α)]]-6- [3- [4-[[(4-cyclohexyl-butyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -4-hexenoic acid;

  [1S- [1α, 2α, 3α, 4α)]-3- [4-[[(4- (Cyclohexylbutyl) -amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] heptane- 2-hexanoic acid or its ester or salt,

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3- [4-[[(4-cyclohexyl-butyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -4-hexenoic acid or an ester or salt thereof;

  [1S- (1α, 2α (Z), 3α (1E, 3S *, 4R *), 4α)] disclosed in US Pat. No. 4,537,981 to Snitman et al., The entire disclosure of which is incorporated herein by reference. ] -7- [3- (3-hydroxy-4-phenyl-1-pentenyl) -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid (SQ29,548) and other 7- Oxabicycloheptane and 7-oxabicycloheptene compounds; disclosed in U.S. Pat.No. 4,416,896 to Nakane et al., The entire disclosure of which is incorporated herein by reference [1S- [1α, 2α (Z), 3α, 4α)]]-7- [3-[[2- (Phenylamino) carbonyl] -hydrazino] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid and other 7- Oxabicycloheptane substituted aminoprostaglandin analogs; disclosed in US Pat. No. 4,663,336 to Nakane et al., The entire disclosure of which is incorporated herein by reference [1S- [1α, 2α (Z), 3α, 4α )]]-7- [3-[[[[(1-oxoheptyl ) Amino] -acetyl] amino] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid and the corresponding tetrazole, and [1S- [1α, 2α (Z), 3α, 4α)]]-7- [3-[[[[[(4-Cyclocyclohexyl-1-oxobutyl) -amino] acetyl] amino] methyl] -7-oxabicyclo] 2.2.1] hept-2-yl] -5 7-oxabicycloheptane substituted diamide prostaglandin analogs such as -heptenoic acid;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3-[[4 as disclosed in US Pat. No. 4,977,174, the entire disclosure of which is incorporated herein by reference. 7- (4-Cyclohexyl-1-hydroxybutyl) -1H-imidazol-1-yl] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -4-hexenoic acid or its methyl ester -Oxabicycloheptaneimidazole prostaglandin analogues;

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3-[[4- (3-Cyclohexyl-propyl) -1H-imidazol-1-yl] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -4-hexenoic acid or its methyl ester;

  [1S- [1α, 2α (X (Z), 3α, 4α)]]-6- [3-[[4- (4-cyclohexyl-1-oxobutyl) -1H-imidazol-1-yl] methyl]- 7-oxabicyclo [2.2.1] hept-2-yl] -4-hexenoic acid or its methyl ester;

  [1S- [1α, 2α (Z), 3α, 4α]]-6- [3- (1H-imidazol-1-ylmethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -4- Hexenoic acid or its methyl ester; or

  [1S- [1α, 2α (Z), 3α, 4α)]]-6- [3-[[4-[[(4-cyclohexyl-butyl) amino] carbonyl] -1H-imidazol-1-yl] methyl -7-oxabicyclo- [2.2.1] -hept-2-yl] -4-hexenoic acid or its methyl ester;

  Including 4- [2- (benzenesulfamido) ethyl] phenoxyacetic acid (BM13,177-Boehringer Mannheim) disclosed in US Pat. No. 4,258,058 to Witte et al., The entire disclosure of which is incorporated herein by reference. Phenoxyalkyl carboxylic acids; 4- [2- (4-chlorobenzenesulfonamido) ethyl] -phenylacetic acid (disclosed in US Pat. No. 4,443,477 to Witte et al., The entire disclosure of which is incorporated herein by reference. Sulfonamidophenyl carboxylic acids including BM 13,505, Boehringer Mannheim); 4- (3-((4-chlorophenyl) sulfonyl) disclosed in U.S. Pat.No. 4,752,616, the entire disclosure of which is incorporated herein by reference. Arylthioalkylphenyl carboxylic acids including) propyl) benzeneacetic acid.

Other examples of thromboxane A ₂ receptor antagonists suitable for use herein include, but are not limited to, bapiprost (which is a preferred example), R68,070-Janssen Research Laboratories (E) -5-[[[[(pyridinyl)] 3- (trifluoromethyl) phenyl] methylene] amino] -oxy] pentanoic acid, 3- [1- (4-chlorophenylmethyl) -5-fluoro-3 -Methylindol-2-yl] -2, -2-dimethylpropanoic acid [(L-655240 Merck-Frosst) Eur. J. Pharmacol. 135 (2): 193, Mar. 17, 87], 5 (Z) -7-([2,4,5-cis] -4- (2-hydroxyphenyl) -2-trifluoromethyl-1,3-dioxane-5-yl) heptenoic acid (ICI185282, Brit. J. Pharmacol. 90 (Proc.Suppl): 228 P-Abs, March 87), 5 (Z) -7- [2,2-dimethyl-4-phenyl-1,3-dioxane-cis-5-yl] heptenoic acid (ICI159995 Brit. J. Pharmacol. 86 (Proc.Suppl): 808P-Abs., December 85), N, N'-bis [7- (3-chlorobenzeneamino-sulfo Nyl) -1,2,3,4-tetrahydro-isoquinolyl] disulfonylimide (SKF 88046, Pharmacologist 25 (3): 116 Abs., 117 Abs, August 83), (1α (Z) -2β, 5α]- (+)-7- [5-[[(1,1'-biphenyl) -4-yl] -methoxy] -2- (4-morpholinyl) -3-oxocyclopentyl] -4-heptenoic acid (AH 23848- Glaxo, Circulation 72 (6): 1208, December 85, Levalorphan allyl bromide (CM32,191 Sanofi, Life Sci. 31 (20-21): 2261, Nov. 15, 82), (Z, 2-endo- 3-oxo) -7- (3-acetyl-2-bicyclo [2.2.1] heptyl-5-hepta-3Z-enoic acid, 4-phenyl-thiosemicarbazone (EP092-Univ. Edinburgh, Brit. Pharmacol. 84 (3): 595, March 85); GR32,191 (bapiprost)-[1R- [1α (Z), 2β, 3β, 5α]]-(+)-7- [5-([1, 1'-biphenyl] -4-ylmethoxy) -3-hydroxy-2- (1-piperidinyl) cyclopentyl] -4-heptenoic acid; ICI192,605-4 (Z) -6-[(2,4,5-cis ) 2- (2-Chlorophenyl) -4- (2-hydroxyphenyl) -1,3-dioxane-5-yl] hexene BAYu3405 (Ramatroban) -3-[[(4-Fluorophenyl) -sulfonyl] amino] -1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid; or ONO3708-7- [2α, 4α -(Dimethylmethano) -6β- (2-cyclopentyl-2β-hydroxyacetamido) -1α-cyclohexyl] -5 (Z) -heptenoic acid; (. +-.) (5Z) -7- [3-endo- ( (Phenylsulfonyl) amino] -bicyclo [2.2.1] hept-2-exo-yl] -heptenoic acid (S-1452, Shionogi domitroban, Anboxan®); (−) 6,8-difluoro-9- p-methylsulfonylbenzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid (L670596, Merck) and (3- [l- (4-chlorobenzyl) -5-fluoro-3-methyl-indole -2-yl] -2,2-dimethylpropanoic acid (L655240, Merck).

  A preferred thromboxane A2 receptor antagonist of the present invention is ifetroban or any pharmaceutically acceptable salt thereof.

In certain preferred embodiments, the preferred thromboxane A2 receptor antagonist is ifetroban sodium ([1S- (1α, 2α, 3α, 4α)]-2-[[3- [4-[(pentylamino) Carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] methyl] -benzenepropanoic acid monosodium salt).
Method of treatment

In certain embodiments of the invention, fibrosis in one or more organs or tissues of a patient or patient population is administered by administering to a patient in need of a therapeutically effective amount of a thromboxane A ₂ receptor antagonist. Methods for prevention and / or treatment and / or amelioration are provided.

Administration of a therapeutically effective amount of a thromboxane A ₂ receptor antagonist is therapeutically useful including but not limited to oral, intranasal, rectal, vaginal, sublingual, buccal, parenteral or transdermal. It can be achieved via any route of administration. In certain preferred embodiments, the thromboxane A ₂ receptor antagonist is administered parenterally. In certain further embodiments, the thromboxane A ₂ receptor antagonist is administered by intra-articular injection. In certain further embodiments, the thromboxane A ₂ receptor antagonist is administered directly to the affected anatomical site. In another embodiment, the thromboxane A ₂ receptor antagonist is administered through the hepatic artery.

In any of the methods described above and others described herein, the thromboxane A ₂ receptor antagonist (e.g., ifetroban) is preferably about 1 ng / ml to about 100,000 ng / ml. Or about 0.1 ng / ml; or about 1 ng / ml to about 10,000 ng / ml for ifetroban itself, and in some embodiments, about 1 ng / ml to about 1,000 ng / ml or more (e.g., some In embodiments, up to about 10,000 ng / ml, in further embodiments up to about 100,000 ng / ml) of plasma concentrations of thromboxane A ₂ receptor antagonists (and / or their active metabolites) To be administered in an effective amount. In some embodiments, the plasma concentration is a steady state plasma concentration. In some embodiments, the plasma concentration is a maximum plasma concentration (Cmax). In certain preferred embodiments where the mammal is a human patient, the therapeutically effective amount is from about 100 mg to about 2000 mg per day, or from about 10 mg or about 100 mg to about 1000 mg per day, and in certain embodiments 1 More preferred is about 100 to about 500 mg per day. The daily dose can be administered in divided doses, or in a single porous dose or unit dose, or multiple doses administered simultaneously. In this regard, ifetroban can be administered orally, intranasally, rectally, vaginally, sublingually, buccal, parenterally or transdermally.

  The dose to be administered should be adjusted according to the age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

In order to obtain the desired plasma concentration of thromboxane A ₂ receptor antagonist for the treatment or prevention of fibrosis, the daily dose of thromboxane A ₂ receptor antagonist is preferably from about 0.1 mg to about It is in the range of 5000mg. In certain preferred embodiments, the daily dose of thromboxane A ₂ receptor antagonist for the treatment or prevention of fibrosis is about 1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 1000 mg per day, It can range from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, or from about 400 mg to about 500 mg.

  In certain preferred embodiments, a daily dose of about 10 mg to about 250 mg (ifetroban free acid amount) of ifetroban sodium produces a therapeutically effective plasma level of ifetroban free acid for the treatment or prevention of fibrosis. .

When the thromboxane A ₂ receptor antagonist is ifetroban, the desired plasma concentration to provide an inhibitory effect of A ₂ / prostaglandin endoperoxide receptor (TPr) activation, and therefore of brain microvascular activation The reduction should be greater than about 10 ng / mL (ifetroban free acid). Some inhibitory effects of thromboxane A ₂ receptor antagonists such as ifetroban may be seen at concentrations greater than about 1 ng / mL.

  The dose to be administered should be carefully adjusted according to the age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

In certain preferred embodiments where the thromboxane A ₂ receptor antagonist is ifetroban or a pharmaceutically acceptable salt thereof, about 10 mg to about 500 mg, preferably about 10 mg to about 300 mg of ifetroban sodium (ifetroban free acid Daily dose) is expected to produce effective plasma levels of ifetroban free acid.
Pharmaceutical composition

The thromboxane A ₂ receptor antagonists of the present invention can be administered by any pharmaceutically effective route. For example, a thromboxane A ₂ receptor antagonist may be formulated for oral, nasal, rectal, vaginal, sublingual, buccal, parenteral or transdermal administration, and thus formulated to suit It can be converted.

In certain embodiments, the thromboxane A ₂ receptor antagonist may be formulated in a pharmaceutically acceptable oral dosage form. Oral dosage forms can include, but are not limited to, oral solid dosage forms and oral liquid dosage forms.

  Oral solid dosage forms can include, but are not limited to, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres and any combination thereof. These oral solid dosage forms can be formulated as immediate release, controlled release, sustained release (sustained release) or modified release formulations.

  The oral solid dosage form of the present invention comprises fillers, diluents, lubricants, surfactants, glidants, binders, dispersants, suspending agents, disintegrants, viscosity-increasing agents, membranes. Pharmaceutically acceptable excipients such as forming agents, granulation aids, flavoring agents, sweetening agents, coating agents, solubilizing agents and combinations thereof may also be included.

  Depending on the desired release profile, the oral solid dosage forms of the invention may contain appropriate amounts of controlled release, sustained release, and controlled release agents.

  Oral liquid dosage forms include, but are not limited to, solutions, emulsions, suspensions and syrups. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those skilled in the art for the preparation of liquid dosage forms. For example, water, glycerin, simple syrup, alcohol and combinations thereof.

In certain embodiments of the invention, the thromboxane A ₂ receptor antagonist may be formulated in a dosage form suitable for parenteral use. For example, the dosage form can be a lyophilized powder, a solution, a suspension (eg, a depot suspension).

In other embodiments, thromboxane A ₂ receptor antagonists can be formulated into topical dosage forms such as, but not limited to, patches, gels, pastes, creams, emulsions, liniments, balms, lotions and ointments.

DETAILED DESCRIPTION The following examples of preferred embodiments is not intended to be limiting and represent specific embodiments of the present invention.

[ Example 1 ]
In this example, ifetroban sodium capsules are prepared with the following ingredients listed in Table 1.

  The sodium salt of ifetroban, magnesium oxide, mannitol, crystalline cellulose and crospovidone are mixed together for about 2 to about 10 minutes using a suitable mixer. The resulting mixture is passed through a 12 to 40 mesh size screen. Thereafter, magnesium stearate and colloidal silica are added and mixing is continued for about 1 to about 3 minutes.

  The resulting homogeneous mixture is then filled into capsules each containing 50 mg of ifetroban sodium salt.

[ Example II ]
In this example, 1000 tablets each containing 400 mg of ifetroban sodium are made from the following ingredients listed in Table 2:

[ Example III ]
In this example, ifetroban sodium injection is prepared intravenously with the following ingredients listed in Tables 3a and 3b:

  The sodium salt of ifetroban, buffer and sodium chloride are dissolved in 3 liters of water for injection, after which the volume is 5 liters. The solution is filtered through sterile filter paper and aseptically filled into pre-sterilized vials and then closed with pre-sterilized rubber stoppers. Each vial contains an active ingredient at a concentration of 50 mg per 5 ml of solution.

[ Example IV ]
The right ventricular adaptation to load stress, improved by thromboxane receptor antagonism , is a direct cause of death in pulmonary arterial hypertension. Prostaglandin / thromboxane equilibrium has been associated with cardioprotective effects under stress, possibly through coronary artery support.
Method:

FVB / N mice or mice with a GFP macrophage specific lineage tracking marker (LysM-Cre) were subjected to pulmonary ligation (or sham operation as a control) to directly increase stress, and from the next day, vehicle, Alternatively, either thromboxane receptor antagonist ifetroban sodium (25 mg / kg / day) in drinking water was given. Two weeks later, noninvasive hemodynamics were obtained by transthoracic echocardiography, and invasive hemodynamics were obtained by right heart pressure-volume catheterization before sacrifice. The heart was evaluated for fibrosis and macrophage infiltration. RNA obtained from the right ventricle was isolated and used to unambiguously find the expression of altered genes using Affymetrix Mouse Gene 2.0 arrays performed in 4 groups (ligated or sham). LysM-Cre mouse hearts were flash-frozen throughout, sectioned, and assessed microscopically for fibrosis and macrophage infiltration. Differences between groups were assessed by ANOVA and t-test. Correlation was evaluated by Spearman correlation.
result:

Ligated mice receiving ifetroban showed that hemodynamic markers of right heart function preserved under stress stress were associated with a decrease in fibrosis and a decrease in recruitment of inflammatory cells. Based on expression arrays, the molecular basis for these effects includes a reduction in pro-fibrotic pathways such as PDGF-D and FBXO32, and inhibitors of THBS4 and TGF-β, asporin and LTBP2. There was in the induction of antifibrotic pathways. There was also evidence of pathway induction for functional hypertrophy, including potential increases in angiogenesis and reactivation of developmental programs related to cardiac myogenesis. All of these changes were specific to ligated mice and were not seen in the sham-operated group that received ifetroban sodium. Since load stress was previously seen to induce thromboxane production, this is likely because the pathway blocked by the drug was not effective in sham surgery.
Conclusion:

  A rodent model of right ventricular stress stress demonstrates that physiological and molecular markers of the adaptive response are improved by the thromboxane receptor antagonist ifetroban sodium.

[ Example V ]
The purpose of this study was to determine whether ifetroban is useful for treating pulmonary hypertension in humans with early stage disease, ifetroban-mediated blockade of thromboxane-prostanoid receptors, To determine whether it may have an effect on heart / lung function and gene expression in a mouse model of pulmonary hypertension.

  Experimental method: In this pulmonary artery ligation (PAB) animal model, we used wild-type or Rosa26-rtTA2 mice on normal diet. Mice were anesthetized at 4-6 months of age and either PAB (20 mice) or sham surgery (10 mice) were performed. Following that procedure, mice were given either ifetroban water or normal drinking water at 30 mg / kg / day, and after 14 days of treatment, we performed cardiovascular phenotyping. After performing a final sacrifice, histology and gene expression array were performed.

  Echocardiograms to assess cardiac output were obtained the day before catheter insertion and sacrifice. The inventors have performed a standard cardiovascular phenotypic test, systemic pressure measurement via tail vein rotator cuff and insertion of an intrajugular cardiac catheter, and right ventricular systolic pressure (RVSP) for peak pressure, diastolic pressure, Continued with measurements of diastolic time constant, arterial elasticity, ejection fraction and stroke volume.

  Following sacrifice, right ventricular hypertrophy was assessed in each animal as a percentage of heart weight. Random fractions of the right heart were fixed in formalin for histological examination and tested for fibrosis index; other hearts were snap frozen via RNA microarray for gene expression analysis. The right heart and lungs were collected for protein expression analysis and gene expression arrays. The left lung was fixed and stained. Platelet deposition was examined in small cell artery blood vessels. The remaining organs were collected and frozen in liquid nitrogen for potential gene expression analysis.

  The results obtained were as follows. Pulmonary artery ligation was successful (ie, right ventricular systolic pressure (RVSP) increased), but ifetroban had no effect. Total cardiac output remained essentially unchanged following ligation, thereby indicating right heart compensation. Tricuspid E to A wave ratio (p <0.05 by independent t test) demonstrated that ifetroban significantly increased the ratio of tricuspid E to A wave in ligated mice. This data suggests that ifetroban increases the size of the heart in the middle of the fibrotic stress factor, which may be advantageous. The results also demonstrate that treatment with ifetroban reduces fibrosis in the ligated right ventricle. A cross section of the right ventricle in mice (Trichrome stained RV taken at 20x) showed that ifetroban reduced fibrosis in the right ventricle for both sham surgery and the ligated right ventricle. Solvent-treated mice increased the level of fibrotic collagen deposition, whereas ifetroban-treated mice had little fibrosis.

  Genes altered by pulmonary ligation and ifetroban treatment are suitable for three general categories: inflammation, fibrosis and muscleization. In general, all three are increased by ligation, but treatment with ifetroban decreases profibrotic and inflammatory gene expression and increases promyogenic gene expression.

  As part of this study, RNA was extracted and expression analysis was performed using a Mouse Genone 2.0 Affymetrix expression array (FIG. 4C). The array design was 2 × 2 × 2: mock / ligation × solvent / ifetroban × M / F. In total, there were 8 arrays; each array was a pool of RV obtained from 3 mice. Only mice with RVSP> 30 were used for the ligation group. Ligation itself changed 199 genes compared with solvent ligation and sham (ABS (mean difference)-sum of standard deviations)> 0.4, and the expression of 49 of those genes was enhanced by ifetroban (Difference> 0.4) and the expression of 29 of these genes was reduced by ifetroban (difference> 0.4). Of the genes whose increase is blocked by ifetroban, it is hypothesized that approximately half show that inflammatory cell recruitment is reduced based on the following facts: (i) Ififetroban is a pro-fibrotic signaling molecule Decreasing the expression of certain PDGF (Ponten et al., “Platelet-dervied growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice”, Circ. Res. 2005 Nov 11:97 (10): Pp. 1036-45), (ii) With respect to fibrosis / antifibrosis, ifetroban reduces the expression of FBX032, a pro-fibrotic signaling molecule (Usui et al., `` Endogenous muscle atrophy F-box mediates pressure overload- induced cardiac hypertrophy through regulation of nuclear factor-kappaB ”, Circ. Res., 2011 Jul 8 09 (2): 161-71), (iii) With respect to fibrosis / antifibrosis, ifetroban is collagen and cell-cell About adhesion Specific genes were, be specifically enhanced expression of thrombospondin -4 (Thbs4). About half of the genes whose increase is enhanced by ifetroban are associated with collagen and cell-cell adhesions: (iv) Ifetroban also enhanced the expression of genes involved in the inhibition of TGF-β, asporin and Ltbp2 (V) ifetroban enhances the expression of other genes, namely Nmrk2, Meox1, Nkd2 and Pkhd1, (vi) with respect to myogenesis, ifetroban enhances the expression of NMRK2, which promotes the progression of muscle differentiation. Can play an important role in regulation (Li et al., `` A novel muscle-specific beta 1 integrin binding protein (MIBP) that modulates myogenic differentiation '', J. Cell Biol. 1999 Dec 27: 147 (7); 391 -8 pages, (vii) With respect to myogenesis, ifetroban enhances expression of Meox1 (Mankoo et al., `` The concerted action of Meox homeobox genes is required upstream of genetic pathways essential for the formation, patterning and differentiation of somites, Development, 2003 Oct: 130 (19): 4655-64; Ifetroban enhances NKD2 expression, Hu et al., “Myristoylated Naked2 antagonizes Wnt-beta-catenin activity by degrading Dishevlled-1 at the plasma membrane” J. Bio. Chem. 2010 April 30: 285 (18), 13561-8, FIG. 12; ifetroban enhances expression of Pkhd1 (Gillessen-Kaesbach et al., “New autosomal recessive lethal disorder with polycystic kidnesy type Potter I, characteristic face, microephaly, brachymelia, and congenital heart defects ", AM J Med Genet., 1993 Feb 15; 45 (4): 511-8.

  Therefore, the protective effect of ifetroban in RV stress is a decrease in the recruitment of inflammatory cells; an induced decrease in pro-fibrotic pathways such as PDGF-D and FBXO32; an inhibitor of THBS4 and TGF-β, asporin And induction of anti-fibrotic pathways including LTBP2; may include induction of pathways associated with functional hypertrophy including potential angiogenesis.

[ Example VI ]
After pulmonary artery ligation was performed on wild type mice, treatment with ifetroban (30 mg / kg / day via drinking water) versus control (ordinary drinking water) was performed for 2 weeks or 6 weeks. Pulmonary artery ligation mimics pulmonary hypertension and right heart failure. Right heart histology revealed a significant increase in cardiomyocyte size in control mice, and ifetroban treatment was able to prevent this effect and showed similar cardiomyocyte size to animals that underwent sham surgery.

  Echocardiography after 6 weeks of treatment / pulmonary artery ligation made the left ventricular failure of control mice significant, while ifetroban-treated mice had similar cardiac function values to animals that received sham surgery.

  Right ventricular systolic pressure (RVSP) was first shown to be elevated (as expected) in all animals undergoing pulmonary artery ligation. Echo data at 6 weeks (including end-diastolic volume, end-systolic volume, left ventricular stroke volume, ejection fraction and shortening rate) show that while the left ventricle is defective in solvent-treated PAB mice, It made significant that ifetroban-treated PAB mice were protected from these effects and had echo values similar to sham-operated animals. By extending pulmonary artery ligation to 6 weeks, the fact that there was left ventricular failure that was not seen in the 2 week model is thought to be surprising and the ability of ifetroban to protect against this left ventricular failure Make it more prominent. Ifetroban also protected against an increase in cardiomyocyte diameter in the right ventricle and reduced right ventricular fibrosis at 6 weeks.

  These results suggest that ifetroban provides protection from dilated cardiomyopathy in this 6-week model via multiple mechanisms / pathways.

[ Example VII ]
In view of the detrimental consequences of TP receptor activation dominance in the state of cardiac stress and the production of isoprostanes associated with cardiomyopathy, we have developed a right ventricular pressure pulmonary artery ligation (PAB) model We tested the effect of TP receptor antagonism in In this example, a solvent or ifetroban was given to mice with RV dysfunction due to pressure loading by pulmonary artery ligation (PAB). Two weeks following PAB, ifetroban treated mice were protected against pressure overload. Gene expression arrays, quantitative histology and morphometry, lineage tracking and cell culture systems were used to determine the mechanism of ifetroban protection. Ifetroban causes near normalization of the fibrotic region, increases RV mass and at the same time prevents cell hypertrophy, increases the expression of anti-fibrotic thrombospodin-4, and promotes fibrosis TGF-β The induction of the pathway was blocked. Low dose aspirin was unable to reproduce these results. Extended treatment with TP receptor antagonists up to 6 weeks after PAB led to further functional indications and reduced the signs of heart failure seen with prolonged pressure overload.

  Male and female age-matched C57B1 / 6 or FVB / NJ mice obtained by self-breeding were used for pulmonary artery ligation. Self-breeding LysM-Cre × mTomato / GFP reporter mouse B6.129P2-Lyz2tm1 (cre) Ifo / J (donated by Tim Blackwell) × Gt (ROSA) 26Sortm4 (ACTB-tdTomato, -EGFP) Luo (JAX stock number 007676) As a result, LysM-GFP mice were obtained. On the day following surgery, mice are treated with 25 mg / kg / day ifetroban (Cumberland Pharmaceuticals Inc., Nashville, TN) drinking water or normal drinking water (solvent) for 2 or 6 weeks prior to hemodynamic assessment. Gave one. Mice were weighed and the water changed once a week.

Results: Increased ventricular efficiency in PAB mice receiving ifetroban Mice received pulmonary artery ligation (PAB) or sham surgery and were treated with solvent in drinking water or ifetroban (a competitive antagonist of TPα / TPβ) for 2 weeks . Right ventricular systolic pressure (RVSP) was elevated in PAB mice, indicating successful mechanical vasoconstriction. Two weeks after ligation, there was no significant change in cardiac output. RV mass was similarly increased in the solvent and ifetroban treated PAB groups. However, by echocardiography, the E / A wave ratio increased in mice given TP antagonists, suggesting that filling efficiency was increased. Western blot analyzed TP receptor expression in RV and remained constant after 2 weeks following PAB treatment or drug treatment.

  PAB showed an increase in RVSP from about 22 mmHg to about 40 mmHg (**, p <0.01 by two-way ANOVA). Cardiac output was not decreased in PAB mice after 2 weeks. The ratio of right ventricular weight to left ventricular + septal weight is increased in PAB mice (**, p <0.01 by two-way ANOVA); this increase is not blocked by ifetroban. The tricuspid E / A ratio, the criterion for contractility, is improved by ifetroban (*, p <.05 by ANOVA), but only in PAB mice. The TP receptor protein is expressed in all RVs and expression does not change with PAB.

Cardiac fibrosis decreased by TP receptor antagonism
30 mmHg RVSP was used to define PAH, and only samples obtained from mice at or above this threshold were used for analysis of the PAB group. PAB mice developed significant RV fibrosis by 2 weeks, which was almost completely extinguished with ifetroban treatment. An oral dose of aspirin (10 mg / kg / day) failed to prevent fibrosis in this model, suggesting that thromboxane A2 is not a ligand that mediates fibrosis. Two weeks after PAB, fibrosis in RV of untreated mice increased from <5% to about 20% (blue staining) in frozen RV tissue sections stained with Masson's trichrome. This effect is blocked by ifetroban, not aspirin.

Changes in RV gene expression in ifetroban-treated PAB mice, through which we determine whether the mechanism by which ifetroban reduced fibrosis and protected RV contractility, with or without drug treatment Gene expression arrays were performed on stored RV sets obtained from mice with sham or PAB surgery. Principal component analysis showed a strong effect of ligation, and only the effect of ifetroban was seen in mice that received ligation. Principal component analysis shows a strong separation of the group with ligation and shows the strong effect of ifetroban only in mice with ligation. Ifetroban did not significantly alter gene expression in mice that received only sham surgery. In PAB mice, ifetroban treatment enhanced transcription of some genes, while the effect of ligation on other genes was blocked by TP receptor antagonism. In particular, there were changes in gene expression related to adhesion, collagen organization, extracellular structure and developmental process.

Cardiac mononuclear cell expression arrays in PAB mice. PAB mice fed ifetroban reduced RV expression of Cd14, a marker for mature macrophages, and Tlr8 and other pro-inflammatory genes. TP receptors are also expressed on mononuclear cells and blockade of these receptors may have an immunospecific effect. To determine whether the decrease in fibrosis seen with TP receptor inhibition was due to reduced macrophage infiltration or proliferation in RV, PAB in LysM-Cre mice expressing eGFP under the lysozyme M promoter was determined. Once done, all cells that always had a mononuclear cell lineage would be labeled with GFP, even if they later differentiated. While most of the mononuclear cells were placed in the left heart or septum, PAB appeared to increase the number of RV mononuclear cells in solvent-treated and aspirin-treated mice. Flow cytometry of RV taken from wild-type mice showed no significant change in ligation in any macrophage population tested, compared to sham-operated controls with solvent treatment rather than ifetroban-treated PAB mice. It was significant to show a non-significant trend for CD14 / CD45 and F480 / CD45 labeled cell expansion and CD86 labeled CD45 + cell decrease. This mismatch to LysM-Cre mice suggests that cells lose their circulating differentiation markers that reside in the heart. Gene expression arrays have shown that ifetroban reduces the expression of genes associated with inflammatory cell recruitment only under pressure overload. Transgenic LysM-Crex flox-mTomato-flox eGFP mice were used to label mononuclear cell-derived cells with RV. Except for cells derived from the mononuclear cell line that expresses fluorescent green (even if they later differentiate), these mice express fluorescent red. PAB significantly increases the number of green cells in vehicle and ASA mice but not in ifetroban treated mice (representative images obtained from 2-3 transgenic hearts shown). Flow selection of total RV for circulating markers found a non-significant trend for increase in PA-ligated mice blocked by ifetroban.

Reduced cell hypertrophy in ifetroban-treated PAB mice Expression of genes related to muscle differentiation was enhanced in PAB mice receiving TP receptor antagonists compared to ligation controls. RV weight was similarly increased in solvent-treated and ifetroban-treated PAB mice, but the increase in cardiomyocyte diameter normally associated with PAB was blocked by ifetroban treatment. Aspirin treated mice had similar cardiomyocyte diameter as solvent treated mice. Cardiomyocyte size is increased in mice with PAB. This effect is blocked by ifetroban, not aspirin. Western blot showed α-MHC and β-MHC expression on RV. While α-MHC is variable but not changed, β-MHC is strongly induced in PAB mice given a TP receptor antagonist. Treatment of ifetroban in PAB mice caused induction of β-myosin heavy chain (β-MHC) protein without change in α-MHC expression. In a pressure-loaded aortic ligation model, this induction is associated with individual hypertrophy that is reduced in β-MHC-expressing cells. Induction of β-MHC after TP receptor antagonism was due to the increase in animal age since the mean age of solvent-treated and ifetroban-treated PAB mice was 688.3 ± 19.8 and 689.8 ± 18.5 days, respectively. There wasn't. Gene expression arrays show ifetroban-induced genes associated with adaptive remodeling, but only under pressure overload.

Reduced TGF-β signaling and enhanced TSP-4 The effects of ifetroban treatment on known fibrotic and anti-fibrotic signaling pathways were tested. Mice receiving TP receptor antagonists have less PAB-related phospho-SMAD2 / 3 than solvent-treated mice, reducing the expression of fibrosis-related genes and increasing the expression of anti-fibrotic genes did. Ifetroban-treated cultured cardiomyocytes given exogenous TGF-β show no change in PAI-1 expression or promoter activity compared to vehicle-treated cells, and TGF-β signaling from its receptor No direct block was indicated, suggesting that in vivo blocking of TGF-β occurs upstream of ligand binding. In contrast to profibrotic TGF-β, pressure overload is associated with the induction of anti-fibrotic thrombospodin-4 (Thbs4; TSP-4) mRNA. Ifetroban treatment potently enhances Thbs4 expression with PAB RV alone (FIG. 6B), which is interpreted as an increase in TSP-4 protein in ifetroban-treated ligated mice. While TSP-4 localization appeared to be limited to fibrotic patches with solvent-treated RV, PAB mice receiving ifetroban showed increased TSP-4 cardiomyocyte expression. Ifetroban blocks phosphorylation of the TGF-β signaling molecule Smad2 / 3 in vivo (each band is obtained from a different mouse heart). Gene expression arrays obtained from RV showed that ifetroban reduced prefibrotic genes and induced antifibrotic genes only under pressure load. In cultured cardiomyocytes, ifetroban does not block protein expression of the canonical TGF-β target PAI1, nor does ifetroban block the induction of luciferase activity induced by the PAI1 promoter. PAB induces TSP-4 expression in RV, which is potently enhanced with ifetroban treatment.

Prevention of heart failure In previous experiments, there was an increase in RV mass, but there was no change in PAB followed by other functional parameters except cardiac output or E / A wave ratio. To determine if the decrease in fibrosis seen with TP receptor antagonism leads to increased preservation of cardiac function, the period following PAB-induced pressure overload is extended to 6 weeks and administered with ifetroban However, it was continued until 6 weeks. After 6 weeks, control treated PAB mice developed left ventricular dilation, as demonstrated by contraction and dilation volume increase, which was accompanied by a compensatory stroke volume increase. This was associated with reduced ejection fraction and shortened rate, which are signs of heart failure. All of these were prevented in PAB mice that received ifetroban in addition to similar RVSP. Mice underwent sham surgery or PAB, and echocardiography and pressure-loop catheterization were performed 6 weeks later. Left ventricular end-diastolic and end-systolic volumes were measured using average values calculated using both spherical and cylindrical models. Echocardiography also provided left ventricular stroke volume and ejection fraction, and percent shortening.

Comparison of high dose versus low dose ifetroban In another arm of this example, low dose (3 mg / kg / day) ifetroban was administered to mice via drinking water for 2 weeks following pulmonary artery ligation. Right ventricular histology revealed that this low-dose treatment did not prevent right ventricular fibrosis. In addition to fibrotic collagen deposition, nuclei were present in the extracellular space obtained from infiltrating or proliferating cells. The results presented earlier herein made significant the anti-fibrotic effect of high dose ifetrobn (25 mg / kg / day) in the same model. Densitometric analysis of thrombospodin-4 (TSP-4) Western blot of right ventricular tissue shows that high-dose ifetroban (25 mg / kg / day) given via drinking water for 2 weeks following pulmonary artery ligation While increasing the expression of anti-fibrotic TSP-4, low dose ifetroban 3 mg / kg / day demonstrates that it did not.

Consideration
The effect of TP receptor antagonism was studied in mice with mechanical contraction of the pulmonary artery, a model of PAH-associated RV hypertrophy. Treatment with an effective amount of the TP receptor antagonist ifetroban decreased RV fibrosis and cardiomyocyte hypertrophy in PAB mice and increased the E / A ratio, one indicator of cardiac efficiency (E / A The ratio is the ratio of early (E) to late (A) ventricular filling rate, in a healthy heart, the E rate is greater than the A rate, and in certain pathologies, with aging, the left ventricular wall is It can become stiff, increasing back pressure when it fills, slowing the early (E) fill rate, thereby reducing the E / A ratio). This was associated with enhanced RV expression of antifibrotic and myogenic genes, as well as decreased expression of genes associated with inflammation and a decrease in RV phospho-SMAD2 / 3. A few differences were seen in sham-operated mice receiving ifetroban, indicating that ifetroban-mediated gene expression changes are specific for PA ligation. When pressure overload was extended to 6 weeks, mice given TP receptor antagonists were protected from the signs of heart failure seen in solvent-treated PAB mice: total increase in left ventricular volume and ejection fraction And reduction in shortening rate. This may be due to ventricular interdependence, septal hallux or neurohormonal activation.

The initial cardioprotective effect seen with TP receptor antagonism was not repeated with low-dose aspirin treatment in mice, suggesting that fibrosis associated with PAB was not mediated by platelet-generating thromboxane. This low dose was chosen because high dose aspirin in heart failure patients does not reduce mortality or hospitalization and to avoid disrupting the anti-inflammatory or salicylic acid mediated NF-κB effects. Either TxA ₂ topical or macrophage production, remain cause potentially cardiac fibrosis observed in this model. However, isoprostanes such as 8-iso-PGF _2α are also known to signal through TP receptors and can cause increased collagen production and fibrogenic effects. Indeed, reducing oxidative stress and isoprostane generation through enhancement of superoxide dismutase or introduction of free radical scavengers may have an antifibrotic cardioprotective effect under pressure overload. There is some controversy as to whether a specific isoprostan signal through the TP receptor or a structurally similar “TP-like receptor” mediates certain isoprostane actions. Tissue-specific receptor complexes can be formed or there can be still unidentified TP-like receptors with similar binding that can play a role in the effects of ifetroban. Alternatively, in addition to isoprostane and thromboxane, the effects of ifetroban can be mediated by another endogenous ligand for TP receptors such as prostaglandin H2 or 20-HETE.

To further complicate the problem, there are splice isomers with α and β isoforms of TP receptors, similar ligand binding and Gq / G ₁₁ coupling, but different localization. Both receptors are effectively blocked by ifetroban. It is not currently known which of these isoforms mediate cardiac fibrosis in which tissue, in response to pressure overload. By both immunoblotting and mRNA (data not shown), we detected robust TP receptor expression on all RVs, although the possible contribution of fibroblasts or endothelial receptors is not negligible , It suggests its expression in cardiomyocytes. However, our method could not distinguish between TPα and TPβ expression.

  In this study, we also examined the effect of TP receptor inhibition on RV macrophage numbers and cell marker expression in PAB mice. By FACS analysis, we found no significant changes not only with ifetroban treatment compared to vehicle, but also between PAB and sham-operated mice. However, hearts taken from mice with GFP-expressing cells of the mononuclear cell line appear to be many mononuclear cells well integrated with cardiomyocyte fibers, and we have found that each RV It was possible that individual mononuclear cells were not completely separated from FACS did not change the percentage of total CD45-expressing cells, including neutrophils, but the LysM-expressing cells visualized in the transgenic heart may actually have been neutrophils.

  Two weeks after PAB, ifetroban treatment increased the E / A wave ratio in PAB mice and showed a possible increase in contraction efficiency. This is similar to previous studies and demonstrates that TP receptor antagonism preserves RV efficiency following endotoxin shock (Lambermont B, Kolh P, Ghuysen A, Segers P, Dogne JM, Tchana-Sato V, Morimont P, Benoit P, Gerard P, Masereel B, and D'Orio V. Effect of a novel thromboxane A2 inhibitor on right ventricular-arterial coupling in endotoxic shock. Shock. 2004; 21: 45-51). It is not known whether this increased efficiency with ifetroban treatment is due to a decrease in cardiac fibrosis, or a decrease in cardiomyocyte hypertrophy associated with PA ligation, or perhaps a combination of these two mechanisms. Although the reduction in cellular hypertrophy we found with ifetroban is consistent with the known hypertrophic effect of TP receptor activation in mice, thromboxane agonists caused hypertrophy of isolated cardiomyocytes in vivo. There was likely a consistent in vivo effect and not due to direct TP receptor inhibition in cardiomyocytes.

  Without changes in α-MHC expression, prevention of individual cell hypertrophy and β-MHC combined RV expression in TP antagonist-treated PAB mice has been previously described by Lopez et al. (Lopez JE, Myagmar B, Swigart PM, Montgomery MD, Haynam S, Bigos M, Rodrigo MC and Simpson PC.β-Myosin heavy chain is induced by pressure overload in a minor subpopulation of smaller mouse cardiac myocytes.Circ Res. 2011; 109: 629-38) Correspond. By sizing individual cardiomyocytes following pressure overload, they found that β-MHC expression occurred only in nonhypertrophic cardiomyocytes; all cells had similar α-MHC expression. Individual cells did not increase in diameter, but PAB mice given ifetroban showed similar increases in RV weight as vehicle-treated mice as evidenced by an increase in Fulton index. Among the genes activated by ifetroban in combination with ligation, there are many genes related to cell growth and reprogramming, and TP receptor inhibition reduces muscle fibrosis in response to pressure overload while also reducing fibrosis. Theories that induce oxidization and functional hypertrophy are established. The ifetroban-initiating event behind the decrease in TGFβ is not yet known, but a decrease in TGFβ activity is probably partly responsible for the decreased fibrotic response.

  TSP-4, augmented by PA ligation and further upregulated with ifetroban treatment, is not known to regulate TGFβ activation, but can itself reduce fibrosis and hypertrophy, pressure overload Increases contractility and cardiac fit. TSP-4 is thought to act by inducing protective endoplasmic reticulum (ER) stress signaling through activating transcription factor 6α (Atf6α), an ER stress response transcription factor. In contrast to the strict fibrosis area in solvent-treated mice, localization of TSP-4 to cardiomyocytes in ifetroban-treated mice supports intracellular signaling in our model Thus, there was no difference in Atf6α mRNA levels after either PA ligation or TP receptor antagonism (data not shown). It is possible that at 2 weeks, any increase in mRNA has been lost, or that the RV stress response is different from the LV model in which the Atf6α response to TSP-4 is depicted.

  In summary, these studies demonstrate that ifetroban is cardioprotective against pressure overload, rather than maladaptive fibrosis, inflammation and cell hypertrophy, rather by directing the right heart to fit. Right heart protection ultimately leads to prevention of left heart failure in these mice.

In the foregoing specification, the invention has been described with reference to specific exemplary embodiments and examples thereof. However, it is evidence that various modifications and changes may be made without departing from the broad concept and scope of the invention as defined in the following claims. This description is not to be taken in a limiting sense, but rather should be considered by way of example.
The present invention includes the following inventions.
(1) treating cardiac fibrosis in a mammal in need of treatment, comprising administering to the mammal a therapeutically effective amount of a thromboxane A ₂ receptor antagonist or a pharmaceutically acceptable salt thereof. Method.
(2) The method according to (1), wherein the mammal is a human patient.
(3) A thromboxane A ₂ receptor antagonist is [1S- (1α, 2α, 3α, 4α)]-2-[[3- [4-[(pentylamino) carbonyl] -2-oxazolyl for mammals. ] -7-Oxabicyclo [2.2.1] hept-2-yl] methyl] -benzenepropanoic acid (ifetroban) or a pharmaceutically acceptable salt thereof.
(4) The method according to (3), wherein the therapeutically effective amount of ifetroban reduces the rate of formation of fibrotic tissue in a mammal.
(5) The method of (3), wherein ifetroban is administered in an amount effective to provide a plasma concentration of ifetroban of about 1 ng / ml to about 10,000 ng / ml.
(6) The method of (3), wherein the thromboxane A ₂ receptor antagonist is administered in an amount effective to provide a plasma concentration of about 1 ng / ml to about 100,000 ng / ml.
(7) The method according to (3), wherein the therapeutically effective amount is about 10 mg to about 1000 mg per day.
(8) The method according to (7), wherein ifetroban is administered orally, intranasally, rectally, vaginally, sublingually, buccally, parenterally, or transdermally.
(9) The method according to (7), wherein the therapeutically effective amount of ifetroban delays the progression of myocardial fibrosis in a human patient.
(10) The method according to (7), wherein the therapeutically effective amount of ifetroban improves exercise capacity in human patients.
(11) The method according to (7), wherein the therapeutically effective amount of ifetroban reduces RV fibrosis in a human patient.
(12) The method according to (7), wherein the therapeutically effective amount of ifetroban reduces cardiomyocyte hypertrophy in a human patient.
(13) The method according to (7), wherein the therapeutically effective amount of ifetroban increases the E / A ratio in a human patient.
(14) Therapeutically effective amount of ifetroban is the right ventricular ejection fraction (RVEF), left ventricular ejection fraction (LVEF), pulmonary dynamics, right ventricular systolic pressure (RVSP), left ventricular systolic function (LVSF) The method according to (7), wherein the function selected from the group consisting of right ventricular diastolic function (RVDF) and left ventricular diastolic function (LVDF) is improved or maintained.
(15) The method according to (14), wherein the therapeutically effective amount of ifetroban increases cardiomyocyte diameter in a human patient.
(16) A therapeutically effective amount of ifetroban is cardioprotective against pressure overload by directing the right heart to adaptation rather than maladaptive fibrosis, inflammation and cellular hypertrophy, (15) The method described in 1.
(17) The method according to (16), wherein the therapeutically effective amount of ifetroban reduces left heart failure in a human patient.
(18) A pharmaceutical composition comprising a thromboxane A ₂ receptor antagonist or a pharmaceutically acceptable salt thereof, wherein the thromboxane A ₂ receptor antagonist requires a right ventricular ejection fraction in a mammal (RVEF), left ventricular ejection fraction (LVEF), pulmonary dynamics, right ventricular systolic pressure (RVSP), left ventricular systolic function (LVSF), right ventricular diastolic function (RVDF) and left ventricular diastolic function (LVDF) A pharmaceutical composition in an amount effective to improve or maintain a function selected from the group consisting of:
(19) The pharmaceutical composition according to (18), wherein the thromboxane A ₂ receptor antagonist is ifetroban or a pharmaceutically acceptable salt thereof.
(20) The pharmaceutical composition according to (19), wherein the ifetroban salt is ifetroban sodium.
(21) The pharmaceutical composition according to (20), wherein the therapeutically effective amount is about 10 mg to about 1000 mg per day.
(22) The pharmaceutical composition according to (21), which is an oral solid dosage form.

Claims (14)

[1S- (1α, 2α, 3α, 4α)]-2-[[3- [4-[(pentylamino) carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl A pharmaceutical composition for treating cardiac fibrosis in a mammal in need of treatment, comprising methyl] -benzenepropanoic acid (ifetroban) or a pharmaceutically acceptable salt thereof. The mammal is a human patient,
Lee Fetoroban or a pharmaceutically acceptable salt thereof is administered in an amount effective to reduce the rate of formation of fibrosis tissue in a mammal, the pharmaceutical composition according to claim 1. 2. The pharmaceutical composition of claim 1 , wherein ifetroban or a pharmaceutically acceptable salt thereof is administered in an amount effective to provide a plasma concentration of ifetroban from about 1 ng / ml to about 10,000 ng / ml. . 2. The pharmaceutical composition of claim 1 , wherein the therapeutically effective amount of ifetroban or a pharmaceutically acceptable salt thereof is about 10 mg to about 1000 mg per day. 5. The pharmaceutical composition according to claim 4 , wherein ifetroban or a pharmaceutically acceptable salt thereof is administered orally, intranasally, rectally, vaginally, sublingually, buccal, parenterally or transdermally. Ifetroban or a pharmaceutically acceptable salt thereof is:
(i) delay the progression of myocardial fibrosis in a human patient, and / or
(ii) improve athletic performance in human patients and / or
(iii) reduce RV fibrosis in human patients, and / or
(iv) reduce cardiomyocyte hypertrophy in human patients, and / or
5. The pharmaceutical composition of claim 4 , wherein (v) the composition is administered in an amount effective to increase the E / A ratio in a human patient. Ifetroban or a pharmaceutically acceptable salt thereof , right ventricular ejection fraction (RVEF), left ventricular ejection fraction (LVEF), pulmonary dynamics, right ventricular systolic pressure (RVSP), left ventricular systolic function (LVSF) The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition is administered in an amount effective to improve or maintain a function selected from the group consisting of right ventricular diastolic function (RVDF) and left ventricular diastolic function (LVDF). object. 8. The pharmaceutical composition of claim 7 , wherein ifetroban or a pharmaceutically acceptable salt thereof is administered in an amount effective to increase cardiomyocyte diameter in a human patient. Effective if ifetroban or a pharmaceutically acceptable salt thereof is cardioprotective against pressure overload by directing the right heart to adaptation rather than maladaptive fibrosis, inflammation and cellular hypertrophy 9. The pharmaceutical composition according to claim 8 , which is administered in an amount. 10. The pharmaceutical composition of claim 9 , wherein ifetroban or a pharmaceutically acceptable salt thereof is administered in an amount effective to reduce left heart failure in a human patient. Right ventricular ejection fraction (RVEF), left ventricular ejection fraction (LVEF), pulmonary dynamics, right ventricular systolic pressure (RVSP), left ventricular systolic function (LVSF), right ventricular diastolic function in mammals in need (RVDF) and left ventricular diastolic function for improving or maintaining the function selected from the group consisting of (LVDF), ifetroban or a pharmaceutically acceptable a pharmaceutical composition comprising a salt thereof. 12. The pharmaceutical composition according to claim 11 , wherein the ifetroban salt is ifetroban sodium. 13. The pharmaceutical composition according to claim 12 , wherein the therapeutically effective amount is from about 10 mg to about 1000 mg per day. 14. The pharmaceutical composition according to claim 13 , which is an oral solid dosage form.